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The Journal of Neuroscience, August 29, 2007, 27(35):9482-9490; doi:10.1523/JNEUROSCI.2287-07.2007

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Neurobiology of Disease
Increasing Sulfatide Synthesis in Myelin-Forming Cells of Arylsulfatase A-Deficient Mice Causes Demyelination and Neurological Symptoms Reminiscent of Human Metachromatic Leukodystrophy

Hariharasubramanian Ramakrishnan,^1 * Kerstin Khalaj Hedayati,^2 * Renate Lüllmann-Rauch,² Carsten Wessig,³ Simon Ngamli Fewou,¹ Helena Maier,¹ Hans-Hilmar Goebel,⁴ Volkmar Gieselmann,¹ and Matthias Eckhardt¹

¹Institute of Physiological Chemistry, Rheinische Friedrich-Wilhelms University of Bonn, 53115 Bonn, Germany, ²Institute of Anatomy, Christian-Albrechts University of Kiel, 24098 Kiel, Germany, ³Department of Neurology, Julius-Maximilians University of Würzburg, 97080 Würzburg, Germany, and ⁴Department of Neuropathology, Johannes Gutenberg University Medical Center, 55131 Mainz, Germany

Correspondence should be addressed to Dr. Matthias Eckhardt, Institut für Physiologische Chemie, Universität Bonn, Nussallee 11, 53115 Bonn, Germany. Email: eckhardt{at}institut.physiochem.uni-bonn.de

Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by the deficiency of arylsulfatase A (ASA). This results in accumulation of sulfated glycosphingolipids, mainly 3-O-sulfogalactosylceramide (sulfatide), in the nervous system and various other organs. In patients, lipid storage causes a progressive loss of myelin leading to various neurological symptoms. The sulfatide storage pattern in ASA-deficient [ASA(–/–)] mice is comparable to humans, but regrettably, the mice do not mimic the myelin pathology. We reasoned that increasing sulfatide storage in this animal model might provoke demyelination. Therefore, we generated transgenic ASA(–/–) [tg/ASA(–/–)] mice overexpressing the sulfatide-synthesizing enzyme galactose-3-O-sulfotransferase-1 in myelinating cells. Indeed, these tg/ASA(–/–) mice displayed a significant increase in sulfatide storage in brain and peripheral nerves. Mice older than 1 year developed severe neurological symptoms. Nerve conduction velocity was significantly reduced in tg/ASA(–/–) mice because of a peripheral neuropathy characterized by hypomyelinated and demyelinated axons. Inhomogeneous myelin thickness in the corpus callosum, increased frequency of hypomyelinated and demyelinated axons in corpus callosum and optic nerve, and substantially reduced myelin basic protein levels are in accordance with loss of myelin in the CNS. Thus, increasing sulfatide storage in ASA(–/–) mice leads to neurological symptoms and morphological alterations that are reminiscent of human MLD. The approach described here may also be applicable to improve other mouse models of lysosomal as well as nonlysosomal disorders.

Key words: arylsulfatase A; cerebroside sulfotransferase; lysosomal storage disorder; metachromatic leukodystrophy; myelin; sulfatide

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Received May 18, 2007; revised July 6, 2007; accepted July 11, 2007.

Correspondence should be addressed to Dr. Matthias Eckhardt, Institut für Physiologische Chemie, Universität Bonn, Nussallee 11, 53115 Bonn, Germany. Email: eckhardt{at}institut.physiochem.uni-bonn.de

This article has been cited by other articles:

				S.-B. Jeon, H. J. Yoon, S.-H. Park, I.-H. Kim, and E. J. Park Sulfatide, A Major Lipid Component of Myelin Sheath, Activates Inflammatory Responses As an Endogenous Stimulator in Brain-Resident Immune Cells J. Immunol., December 1, 2008; 181(11): 8077 - 8087. [Abstract] [Full Text] [PDF]

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